To our practical knowledge ths s the frst tme ths drug s utilized aganst ALL cells.NVBAG956 was manly cytostatc ALL cell lnes and was not a strong nducer of apoptoss.nevertheless, t potently nduced apoptoss ALL prmary cells, ncludng a cell subset thaenrched putatve LCs.GDC 0941 s anhbtor of class P3K thathas entered clncal trals for sold tumors.ALL cell lnes and patent samples, GDC 0941 dsplayed a weak cytostatc result.MOLT four cells have been far more senstve to GDC 0941 thathe other cell lnes.The allosterc Akt nhbtor MK 2206, thapresently undergong clncal trals for that treatment method of sold tumors, was much more potent thaGDC 0941 both ALL cell lnes and prmary samples.Aside from beng cytostatc, MK 2206 also nduced apoptoss.Surprsngly, we uncovered that RAD 001 was additional effective thaKU 63794, aATcompettve mTORC1 mTORC2 nhbtor, especally MOLT 4 cells.ndeed, ATcompettve mTORC1 mTORC2 nhbtors are generally consdered to become more powerful tharapamycand rapalogs.nonetheless, RAD 001 and KU 63794 dsplayed almost smar weak potency aganst ALL lymphoblasts.
Anterestng observatos that RAD 001 treatment method resulted Ser 473 Akt dephosphorylatoALL cell lnes.most cancer cell kinds, rapalogs which include RAD 001, ncreased Akt phosphorylatothrough nhbtoof a negatve feed back loobased omTORC1 p70S6K RS1 P3K.nhbtoof this kind of a negatve feed back loouregulates mTORC2 dependent phosphorylatoof Akt oSer 473 and ncreases cell survval.nevertheless, the rapalog nhbtor CC inhibitor PLX4032 779has beereported Odanacatib to result in mTORC2 dsassembly and Ser 473 Akt dephosphorylaton.As a result, t might be that RAD 001 dsassembled mTORC2 complicated ALL cell lnes.Ths fndng seems also to ndcate that rapamycand RAD 001 results are usually not supermposable, as rapamyctreatment of ALL cell lnes, below the exact same condtons employedhere as for RAD 001, dd not result Ser 473 Akt dephosphorylatothe same ALL cell lnes.A rapdly emergng theme targeted therapy of P3K Akt mTOR sgnalng, s that combned vertcal nhbtoat dfferent nodes of the cascade ofteleads to greater outcomes that the utilization of ether sngle or dual nhbtors.
however, nearly all of the studes carried out ths feld so far took advantage of sold tumor designs.So far as we know, ths s the frst report whch documented the superor effcacy of vertcal targetng of the P3K Akt mTOR pathway ALL cell lnes.Prevous evdencehas demonstrated that the P3K Akt mTOR network s characterzed by multple feed back loops that fnely act to manage

sgnal transducton.hence, the exstence of these loops could lmt the anttumor results of P3K Akt mTOR nhbtors gvemonotherapy settngs, and explans the mportance of testng the results of combnatotreatment.Consequently, nhbtng on the exact same tme at dfferent levels and wth dfferent nhbtors the P3K Akt mTOR pathway s a possble technique to enhance ther effectveness oleukemc cells.outstanding that ALL cell lnes, a synergsm was detected for drugs used at varous concentratons that were consderably beneath the C50 of the drugs wheadmnstered alone.